"Cardiofaciocutaneous Syndrome" – What Is It?

Cardiofaciocutaneous syndrome (CFC syndrome) belongs to the group of RASopathies, which are based on genetic changes in the so-called RAS/MAPK signaling pathway. This signaling pathway ensures the transmission of information within the cell. In CFC syndrome, genetic mutations are known in four different genes: BRAF (CFC1), KRAS (CFC2), MAP2K1 (CFC3), and MAP2K2 (CFC4). Clinically, it is characterized by various heart defects, a characteristic facial appearance, skin abnormalities, muscular and skeletal changes, neurological anomalies, and developmental delay.

Overview of the Chapters on This Page:

  • Cardiofaciocutaneous Syndrome – What Is It? (This Section)
  • How Is "Cardiofaciocutaneous Syndrome" Diagnosed?
  • What Is the Risk of Cancer?
  • What Is Known About the Development of "Cardiofaciocutaneous Syndrome"
  • Is There Any Treatment Available?
  • Medical Measures for Early Detection
  • Cardiofaciocutaneous Syndrome – What You Can Do Yourself
  • Links and Further Information (e.g., From Support Groups)
  • Cardiofaciocutaneous Syndrome – What Is It? (This Section)
  • How Is "Cardiofaciocutaneous Syndrome" Diagnosed?
  • What Is the Risk of Cancer?
  • What Is Known About the Development of "Cardiofaciocutaneous Syndrome"?
  • Is There Any Form of Treatment Available?
  • Medical Measures for Early Detection
  • Cardiofaciocutaneous Syndrome – What You Can Do Yourself
  • Links (e.g., From Support Groups) and Further Information

How Is "Cardiofaciocutaneous Syndrome" Diagnosed?

To date, there are no diagnostic criteria for CFC syndrome, so a suspected diagnosis is usually made based on conspicuous clinical findings and confirmed by genetic diagnostics.

Suspected Diagnosis

CFC syndrome is suspected if the following findings are present:

Heart:

  • Pulmonary stenosis (narrowing of the outflow tract from the right ventricle to the pulmonary artery)
  • Atrial septal defect (hole in the cardiac septum between the two atria of the heart)
  • Ventricular septal defect (hole in the ventricular septum between the two chambers of the heart)
  • Hypertrophic cardiomyopathy (thickening of the heart muscles, usually of the left ventricle)
  • Heart valve defects
  • Rhythm disturbances

Head and Face:

  • Large head
  • High and broad forehead and bilateral indentations in the area of the temples
  • Underdeveloped over-eye bulge
  • Sparse or missing eyebrows
  • Wide eye distance and sloping palpebral fissures
  • Eye abnormalities: squinting, eye twitching, short-sightedness or long-sightedness, drooping eyelid, astigmatism)
  • Short nose with sunken nasal root and upturned nostrils
  • Prominent and wide philtrum (groove between nose and upper lip), pointed arched palate
  • Low-set, backward-rotated ears

Skin, Hair, Nails:

  • Skin: Dry skin, excessive keratinization of the skin on the palms of the hands and feet as well as on the arms, legs, and face, thickened hair follicles, eczema, blood sponges, café-au-lait spots, redness, pigmentation spots
  • Hair: Sparse, frizzy, thin or thick, woolly or brittle hair; sparse or missing eyebrows and eyelashes
  • Nails: Underdeveloped, flat, broad nails; rapid nail growth

Other Conspicuous Features:

  • Muscles/skeleton: Short neck, wing fur on the neck, deformed ribcage, deformations of the spine, flat feet
  • Neurology: mainly mild to severe developmental delay and muscular weakness
  • Gastrointestinal tract: failure to thrive, gastroesophageal reflux (reflux of stomach contents into the esophagus), vomiting and constipation
  • Short stature

Genetic Diagnostics

The diagnosis of “CFC syndrome” is confirmed if a mutation, i.e., genetic change in the BRAF, KRAS, MAP2K1, or MAP2K2 gene, is detected.

What Is the Risk of Cancer?

Cancers can occur as part of a CFC syndrome, but this is only rarely the case. Exact figures on the incidence of cancer do not currently exist. Leukemia, lymphoma, hepatoblastoma (liver tumor) and rhabdomyosarcoma (soft tissue tumor) have been described to date.

Clinically, the following manifestations are also prominent in the various age groups:

Pregnancy and Newborn Period

In most cases, there is an above-average amount of amniotic fluid during pregnancy. In newborns, the characteristic shape of the face is already noticeable (see “Diagnosis”), and malformations of the heart are usually already apparent at birth. Feeding difficulties can also be a problem in the neonatal period.

Infancy

Major difficulties with food intake can still occur in infants, which may require feeding via a tube. Gastroesophageal reflux (reflux of stomach contents into the esophagus) and constipation may also occur. Overall, this can fail to thrive.

All children with CFC syndrome have a neurological abnormality in the form of a psychomotor developmental delay with muscular weakness and delayed speech development or learning disabilities. The intensity can range from mild to extremely severe, with some patients having a normal IQ.

Childhood and Adolescence

The following manifestations can occur at this age:

  • Difficulties with food intake
  • Short stature: In almost all children and adolescents with CFC syndrome
  • Psychomotor developmental delay of varying degrees from mild to very severe, mainly affecting motor skills and speech
  • Seizures: Around 50% of CFC patients suffer from seizures, which usually occur for the first time in infancy or early childhood but can also develop later in childhood.
  • ENT: Frequent middle ear infections and narrowed external auditory canal
  • Eye: strabismus, eye twitching, underdeveloped optic nerve, astigmatism, short- or long-sightedness
  • Heart: 75-80% of CFC patients have cardiac manifestations such as thickening of the heart muscle, structural abnormalities, and, less frequently, arrhythmias.
  • Kidney/urogenital tract: In up to 33% of CFC patients as “abdominal testicles” (testicles are located in the abdominal cavity) in male patients as well as kidney cysts and kidney stones, water sac kidney, and dilated ureter due to urinary retention
  • Blood: Von Willebrand syndrome (coagulation disorder) has been described
  • Skin: Dry skin and thickened hair roots improve with increasing age so that hair growth is increasingly possible. Excessive keratinization on the palms of the hands and feet and lymphoedema increase with age. Pigment spots become more numerous with age. There is also a tendency towards severe skin infections.
  • Musculature/skeleton: In the majority of CFC patients, muscular involvement is present in the form of muscle weakness, reduced muscle mass, and overstretched joints. Skeletal changes may include thoracic deformities, spinal deformities, or a restricted gait.
  • Appearance: With increasing age, the characteristic shape of the face (see “Diagnosis”) becomes less conspicuous.

CFC syndrome occurs equally in males and females.

What Is Known About the Development of "Cardiofaciocutaneous Syndrome?"

CFC syndrome is caused by mutations, i.e., genetic changes in the BRAF, KRAS, MAP2K1, or MAP2K2 genes. These genes code for proteins of the so-called RAS/MAPK signaling pathway, which mediates information in our cells.

If one of the genes is now present in an altered form, the corresponding protein is also not produced correctly and can no longer fulfill its actual function. This results in incorrect information transfer within the cell, leading to congenital anomalies and developmental delays.

Several hundred people are probably affected with CFC syndrome worldwide, but the general incidence of the disease is not known. It can be passed on from parents to their children, and the inheritance is autosomal dominant. Spontaneous or new mutations often occur, called de novo mutations.

Is There Any Form of Treatment Available?

Given the large number of possible manifestations, treatment should always be symptom-oriented and carried out in collaboration with various specialist disciplines.

Diagnosis of " Cardiofaciocutaneous Syndrome" What's Next?

If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.

Diagnosis of " Cardiofaciocutaneous Syndrome" What's Next?

If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.

Medical Measures for Early Detection

Regular clinical examinations should be conducted to record abnormalities of the gastrointestinal tract, growth, cognitive development, and changes to the muscles and skeleton.

In addition, regular cardiologic, neurologic, ENT, ophthalmologic, and dermatologic examinations should be carried out.

Patients should be made aware of a possible increased risk of leukemia, lymphoma, liver, and soft tissue tumors. Targeted cancer screening is not recommended.

Cardiofaciocutaneous Syndrome- What You Can Do Yourself

You Should Pay Attention to This

Patients with CFC syndrome report heat intolerance, which is why strong heat exposure should be avoided.

You should consult a doctor as soon as seizures, abnormalities of the skin, visual or hearing difficulties and changes or pain in muscles or bones occur. However, non-specific symptoms such as abdominal, flank or bone pain, tiredness or weakness should also be noticed and reported to a doctor. You should also consult a doctor if you experience any other new abnormalities or complaints.

Further Information

Any further questions?

You can reach us by e-mail and telephone. You can also visit us in person during our consultation hours. For further information, please refer to our contact page.